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Multiple Myeloma, Gammopathies

Hyperhaploidy is a novel high-risk cytogenetic subgroup in multiple myeloma

Leukemia volume 31, pages 637–644 (2017)Cite this article

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Abstract

Hyperhaploid clones (24–34 chromosomes) were identified in 33 patients with multiple myeloma (MM), demonstrating a novel numerical cytogenetic subgroup. Strikingly, all hyperhaploid karyotypes were found to harbor monosomy 17p, the single most important risk stratification lesion in MM. A catastrophic loss of nearly a haploid set of chromosomes results in disomies of chromosomes 3, 5, 7, 9, 11, 15, 18, 19 and 21, the same basic set of odd-numbered chromosomes found in trisomy in hyperdiploid myeloma. All other autosomes are found in monosomy, resulting in additional clinically relevant monosomies of 1p, 6q, 13q and 16q. Hypotriploid subclones (58–68 chromosomes) were also identified in 11 of the 33 patients and represent a duplication of the hyperhaploid clone. Analysis of clones utilizing interphase fluorescence in situ hybridization (iFISH), metaphase FISH and spectral karyotyping identified either monosomy 17 or del17p in all patients. Amplification of 1q21 was identified in eight patients, demonstrating an additional high-risk marker. Importantly, our findings indicate that current iFISH strategies may be uninformative or ambiguous in the detection of these clones, suggesting this patient subgroup maybe underreported. Overall survival for patients with hyperhaploid clones was poor, with a 5-year survival rate of 23.1%. These findings identify a distinct numerical subgroup with cytogenetically defined high-risk disease.

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Acknowledgements

We thank the patients and staff of the Myeloma Institute for Research and Therapy. This work was supported in part by PO1 Grant CA 0055819 from the National Cancer Institute.

Author contributions

JRS analyzed and interpreted data and wrote the manuscript. CMS, CS, CLH, LP, ML, GS and JDS analyzed data. ET performed iFISH and JLL performed mFISH and SKY studies. JE, CS and CB provided statistical analysis. MZ, FED, FvR and BB provided patient samples. BB and GJM wrote and reviewed the manuscript.

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Authors and Affiliations

  1. Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    J R Sawyer, C M Swanson, C Stangeby, C L Hale, L Parr, M Lynn, G Sammartino & J L Lukacs

  2. Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    J R Sawyer, E Tian, J Epstein, C Stein, C Bailey, M Zangari, F E Davies, F Van Rhee, B Barlogie & G J Morgan

  3. Signal Genetics Inc., Carlsbad, CA, USA

    J D Shaughnessy Jr

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Correspondence to J R Sawyer.

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Sawyer, J., Tian, E., Shaughnessy Jr, J. et al. Hyperhaploidy is a novel high-risk cytogenetic subgroup in multiple myeloma. Leukemia 31, 637–644 (2017). https://doi.org/10.1038/leu.2016.253

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